Our previous studies showed that the (+)-isomers of naloxone and naltrexone (that do not act on opioid receptors) suppress elevation of dopamine in the nucleus accumbens by cocaine and morphine by a Toll-4/MD2 dependent mechanism. In the present work, we used intracellular recording of evoked GABAergic inhibitory postsynaptic potentials (eIPSPs) in central amygdala (CeA) neurons to examine the role of TLR4 activation by lipopolysaccharide (LPS). We also studied deletion of the LPS adapter protein CD14 in acute ethanol effects on the GABAergic system. Using a combination of pharmacological blockade of the Toll-4/MD2 system and CD14 knockout mice, we showed that TLR4/MD2 and CD14 play a substantial role in the acute effects of ethanol and suggesting that drugs acting on these two systems may be useful agents for the treatment of alcohol abuse. Earlier work has implicated neurokinin-1 receptors (NK1Rs) in the mediation of alcohol and opiate, but not cocaine reward in rodents. We showed earlier that NK1R antagonism also blocks stress-induced reinstatement of alcohol seeking in rats. Other studies have found that substance P (SP) infusion directly into the brain reinstates cocaine seeking following extinction. We earlier synthesized the NK1R antagonist L822429 and have now utilized this antagonist to examine the question of whether on yohimbine-induced reinstatement of alcohol or cocaine seeking can be blocked with L822429 in the rat. We found that L822429 attenuates yohimbine-induced reinstatement of alcohol seeking, but does not affect baseline alcohol self-administration. Our studies also showed that L822429 suppresses of yohimbine-induced reinstatement of cocaine seeking by L822429, suggesting that the NK1R receptor is involved in stress-induced seeking of both drugs.